Citations

We conducted a comprehensive screening of rare coding variants in an African American cohort to identify novel pathogenic mutations within the early-onset Alzheimer’s disease (EOAD) genes ( APP, PSEN1 , and PSEN2) in this understudied population. Whole-exome sequencing of 238 African American subjects identified 6 rare missense variants within the EOAD genes, which were observed in AD cases but never among controls. These variants were analyzed in an independent cohort of 300 African American subjects in which PSEN2 :NM_000447:exon5:c.T331C:p.Phe111Leu and PSEN1-minilin rs777923890 variants were again not observed, indicating that these novel rare variants, may contribute to AD risk in this population.

The proliferation of new endovascular devices and therapeutic strategies calls for a prudent and rational evaluation of their clinical benefit. This evaluation must be done in an effective manner and in collaboration with industry. Such research initiative requires organisational and methodological support to survive and thrive in a competitive environment. We propose the formation of an international consortium, an academic alliance committed to the pursuit of effective neurovascular therapies. Such a consortium would be dedicated to the design and execution of basic science, device development and clinical trials. The Consortium is owned and operated by its members. Members are international leaders in neurointerventional research and clinical practice. The Consortium brings competency, knowledge, and expertise to industry as well as to its membership across a spectrum of research initiatives such as: expedited review of clinical trials, protocol development, surveys and systematic reviews; laboratory expertise and support for research design and grant applications to public agencies. Once objectives and protocols are approved, the Consortium provides a stable network of centers capable of timely realization of clinical trials or preclinical investigations in an optimal environment. The Consortium is a non-profit organization. The potential revenue generated from client-sponsored financial agreements will be re-directed to the academic and research objectives of the organization. The Consortium wishes to work in concert with industry, to support emerging trends in neurovascular therapeutic development. The Consortium is a realistic endeavour optimally structured to promote excellence through scientific appraisal of our treatments, and to accelerate technical progress while maximizing patients' safety and welfare.

Background: Nurse practitioners (NPs) and physician assistants (PAs) are increasingly utilized in health care. However, their roles in liver transplantation (LT) have not been investigated. Materials and Methods: In this study, we reviewed the employment and development of NPs and PAs and their impact on our deceased-donor LT (DDLT) program. Results: We found a safe and efficient way to utilize NPs and PAs in a DDLT program. Since the beginning of our program, Model of End-Stage Liver Disease (MELD) scores have increased significantly, suggesting patients are sicker at the time of transplant, and wait times of patients have become longer. With the incorporation of NPs and PAs, we found that length of stay (LOS) was not affected. The overall median warm ischemic time did not increase. Outcomes of LT for both patient and graft survival actually improved and remain at or above the expected values. These results collectively support the usefulness and validity of NPs and PAs in a DDLT program. Conclusion: We have determined that surgical and medical NPs and PAs are essential for optimal patient outcomes. They facilitate a better learning experience for residents and fellows on their transplant rotations. Further investigations to assess the roles of these providers and their impact on the education of residents and fellows in transplantation are warranted. Further transplant hepatology education programs and/or fellowships are recommended to assist in the education and professional development of transplant NPs and PAs.

AbstractBackgroundAnimal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis.MethodsFull thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti‐inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index.ResultsBoth diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti‐inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206‐positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04).ConclusionLoss of antral CD206‐positive anti‐inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.

OBJECTIVE Defects in the apoptotic machinery and augmented survival signals contribute to drug resistance in glioblastoma (GBM). Moreover, another complexity related to GBM treatment is the concept that GBM development and recurrence may arise from the expression of GBM stem cells (GSCs). Therefore, the use of a multifaceted approach or multitargeted agents that affect specific tumor cell characteristics will likely be necessary to successfully eradicate GBM. The objective of this study was to investigate the usefulness of sulforaphane (SFN)—a constituent of cruciferous vegetables with a multitargeted effect—as a therapeutic agent for GBM. METHODS The inhibitory effects of SFN on established cell lines, early primary cultures, CD133-positive GSCs, GSC-derived spheroids, and GBM xenografts were evaluated using various methods, including GSC isolation and the sphere-forming assay, analysis of reactive oxygen species (ROS) and apoptosis, cell growth inhibition assay, comet assays for assessing SFN-triggered DNA damage, confocal microscopy, Western blot analysis, and the determination of in vivo efficacy as assessed in human GBM xenograft models. RESULTS SFN triggered the significant inhibition of cell survival and induced apoptotic cell death, which was associated with caspase 3 and caspase 7 activation. Moreover, SFN triggered the formation of mitochondrial ROS, and SFN-triggered cell death was ROS dependent. Comet assays revealed that SFN increased single- and double-strand DNA breaks in GBM. Compared with the vehicle control cells, a significantly higher amount of γ-H2AX foci correlated with an increase in DNA double-strand breaks in the SFN-treated samples. Furthermore, SFN robustly inhibited the growth of GBM cell–induced cell death in established cell cultures and early-passage primary cultures and, most importantly, was effective in eliminating GSCs, which play a major role in drug resistance and disease recurrence. In vivo studies revealed that SFN administration at 100 mg/kg for 5-day cycles repeated for 3 weeks significantly decreased the growth of ectopic xenografts that were established from the early passage of primary cultures of GBM10. CONCLUSIONS These results suggest that SFN is a potent anti-GBM agent that targets several apoptosis and cell survival pathways and further preclinical and clinical studies may prove that SFN alone or in combination with other therapies may be potentially useful for GBM therapy.

Purpose: To present the most updated American College of Radiology consensus guidelines formed from an expert panel on treatment of locally advanced, high-risk prostate cancer Methods: The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. Results: The panel summarized the most recent and relevant literature on the topic and voted on 4 clinical variants illustrating the appropriate management of locally advanced, high-risk cancer. Numerical rating and commentary reflecting the panel consensus was given for each treatment approach in each variant. Conclusions: Aggressive local approaches including surgery followed by adjuvant XRT, beam combined with androgen deprivation therapy, and beam combined with brachytherapy have resulted in unpresented success in locally advanced, high-risk prostate cancer. By combining most recent medical literature and expert opinion, this guideline can aid clinicians in the appropriate integration of available therapeutic modalities.

SummaryShiitake dermatitis is a rare cutaneous reaction to lentinan, a polysaccharide component in the cell walls of shiitake mushrooms (Lentinula edodes). Herein, we systematically review the case report and case series English‐language literature on shiitake dermatitis, which refers to a total of 50 patients (38 males, 12 females; mean age: 44.58 years). The majority of cases occurred after the consumption of raw mushrooms, whereas 22% of cases were caused by the eating of lightly or undercooked mushrooms. The most common clinical presentations, localized symptoms, and systemic findings include linear flagellated dermatitis (98%), pruritus (78%), and fever, diarrhea, and mucosal ulcers, respectively. The diagnosis of this entity continues to be based on clinical findings as laboratory abnormalities, and the findings of skin biopsies and patch/prick tests are nonspecific and inconsistent. The condition is self‐limiting, resolving in approximately 12.5 d without treatment. Based on the included case reports, it appears that medical treatment may slightly shorten the course of disease (to 9–11 d, varying by therapy) but should be considered on an individual patient basis. However, the treatment of symptoms, reassurance, and the avoidance of re‐exposure are sufficient treatment recommendations for this condition.

The use of liver grafts from donation after cardiac death (DCD) has been limited due to the increased rate of graft failure, mostly related to ischemic cholangiopathy (IC). It is our hypothesis that longterm outcomes and quality of life (QOL) similar to patients undergoing liver transplantation (LT) with donation after brain death (DBD) can be achieved. Clinical outcomes of all patients undergoing DCD LT (n = 300) between 1998 and 2015 were compared with a propensity score–matched cohort of patients undergoing DBD LT (n = 300). Patients were contacted for a follow‐up questionnaire and short‐form (SF)–12 QOL Survey administration. Median follow‐up was >5 years. Graft survival at 1‐, 3‐, and 5‐years was 83.8%, 75.5%, and 70.1% in the DCD LT group and 88.4%, 80.3%, and 73.9% in the DBD LT group ( P = 0.27). Patient survival at 1‐, 3‐, and 5‐years was 92.3%, 86.1%, and 80.3% in the DCD LT group and 92.3%, 85.1%, and 79.5% in the DBD LT group ( P = 0.81). IC developed in 11.7% and 2% of patients in the DCD LT group and DBD LT group, respectively ( P < 0.001). DCD LT recipients who developed IC had inferior graft survival compared with both the DCD non‐IC group ( P < 0.001) and the DBD LT group ( P < 0.001); no difference in graft survival was observed between the DCD non‐IC group and the DBD LT group ( P = 0.50). Physical and Mental Composite Scores on the SF‐12 QOL questionnaire were similar between the DCD LT and DBD LT groups (44.0 versus 45.4; P = 0.34 and 51.9 versus 52.2; P = 0.83), respectively. Similar longterm survival and QOL scores can be achieved between DCD LT and DBD LT. Prevention of IC in DCD LT yields excellent graft and patient survival with virtually no difference compared with DBD LT. Liver Transplantation 23 342–351 2017 AASLD .